ClinVar Miner

Submissions for variant NM_000091.4(COL4A3):c.4981C>T (p.Arg1661Cys) (rs201697532)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000516971 SCV000341862 likely pathogenic not provided 2016-06-01 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000283598 SCV000537703 likely pathogenic Alport syndrome, autosomal recessive 2016-07-11 criteria provided, single submitter clinical testing This heterozygous missense variant in the COL4A3 gene (autosomal recessive transmission) is present in a male patient with Alport syndrome who also harbours a non-sense variant in the same gene (see below). The segregation analysis could not be done, but regarding the clinical presentation of the patient, it is assumed that these two variants are present in compound heterozygosity
Athena Diagnostics Inc RCV000516971 SCV000612952 pathogenic not provided 2014-11-25 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000677316 SCV000803483 uncertain significance Alport syndrome 3, autosomal dominant 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Alport syndrome, autosomal recessive, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:24052634). BS2-Supporting => BS2 downgraded in strength to supporting.
Gharavi Laboratory,Columbia University RCV000516971 SCV000809140 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Invitae RCV000516971 SCV000947691 pathogenic not provided 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1661 of the COL4A3 protein (p.Arg1661Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201697532, ExAC 0.05%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in an individuals affected with Alport syndrome (PMID: 24052634). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been observed in several individuals with Alport syndrome (PMID: 26809805, 11134255, Invitae). ClinVar contains an entry for this variant (Variation ID: 287915). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, Klinikum rechts der Isar RCV000283598 SCV001149721 likely pathogenic Alport syndrome, autosomal recessive 2020-01-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001141624 SCV001301983 uncertain significance Alport syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Biology Laboratory, Fundació Puigvert RCV000283598 SCV001425009 likely pathogenic Alport syndrome, autosomal recessive 2020-02-01 criteria provided, single submitter research
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000677316 SCV001427178 likely pathogenic Alport syndrome 3, autosomal dominant 2019-02-10 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_000091.4(COL4A3):c.4981C>T, has been identified in exon 52 of 52 of the COL4A3 gene. The variant is predicted to result in a major amino acid change from arginine to cysteine at position 1661 of the protein (NP_000082.2(COL4A3):p.(Arg1661Cys)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the C4 functional domain. In silico predictions for this variant are consistently pathogenic (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD database at a frequency of 0.036% (99 heterozygotes; 1 homozygote). An alternative residue change to histidine has been reported in the gnomAD database at a frequency of 0.0032%. The variant has previously been described as pathogenic in multiple patients with Alport syndrome and segregated with disease in both heterozygous and compound heterozygous states, however it has also recently been reported as a Variant of Uncertain Significance (ClinVar, Heidet, L. et al. (2001), Storey, H. et al. (2013), Malone, A. et al. (2014), Braunisch, MC. et al. (2018)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000283598 SCV001623176 likely pathogenic Alport syndrome, autosomal recessive 2021-04-16 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.4981C>T (p.Arg1661Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 249438 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in COL4A3 causing Autosomal Recessive Alport Syndrome (0.0019), allowing no conclusion about variant significance. The c.4981C>T has been reported in the literature in at least three individuals affected with Autosomal Recessive Alport Syndrome with other (likely) pathogenic COL4A3 variants in trans (Storey_2013, ClinVar: SCV000537703.1). In addition, the variant was also reported in several individuals affected with Alport syndrome where the other variant in trans was not specified (e.g. Heidet_2001, Weber_2016, Savige_2016). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2) / likely pathogenic (n=6) or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000677316 SCV001192760 likely pathogenic Alport syndrome 3, autosomal dominant 2019-07-25 no assertion criteria provided clinical testing
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001141624 SCV001449247 uncertain significance Alport syndrome 2017-10-12 no assertion criteria provided clinical testing This individual is also heterozygous for the c.4981C>T p.(Arg1661Cys) variant in the COL4A3 gene. This variant has been reported in the gnomAD browser ( with an allele frequency of 0.059% (76/126650 alleles including one homozygote). It has also been previously described in the literature in patients with Alport syndrome with both autosomal dominant and recessive inheritance (Heidet et al 2001 J Am Soc Nephrol 12:97, Storey et al 2013 J Am Soc Nephrol 24:1945, Malone et al 2014 Kidney Int 86:1253). This variant is reported in ClinVar as likely pathogenic in two individuals, however no details were provided. In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster suggest that this variant is likely to be pathogenic. As Alport syndrome due to COL4A3 variants can be autosomal dominant or recessive it is not clear if this variant is disease causing. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines.

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